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How Sleep Refreshes Our "Etch-A-Sketch" Brains

For the first time, scientists have watched sleep transform the brain. The research confirms a long-standing theory about the value of sleep—and helps explain why sleep deprivation messes with our ability to remember.

SPOTLIGHT INDEX

ANYONE WHO HAS PULLED AN ALL-NIGHTER knows that our mental abilities take a hit after a sleepless night. But why? What makes sleep so restorative?

The answer may be that shut-eye is a biological trade-off for the ability to learn and remember.

Two independent teams of researchers recently showed that sleep streamlines synapses, the junctions between neurons that control the flow of information between neighboring cells. One study found that synapses, which grow when animals are awake and learning, shrink during sleep, so they are ready in the morning to be exercised again. And another showed that the levels of synaptic proteins, which build during waking hours, drop during sleep, and that if this reset process is prevented, mice cannot form new memories.

To learn more about what these findings mean, and how they might be used, The Kavli Foundation spoke to the scientists who conducted this new research, as well as an expert on the relationship between sleep and memory in humans.

The participants were:

CHIARA CIRELLI, MD, PhD—is a professor of psychiatry at the University of Wisconsin-Madison, where she co-leads the Wisconsin Center for Sleep and Consciousness, with her long-time collaborator, Giulio Tononi.

GRAHAM DIERING, PhD—is a post-doctoral fellow in the Huganir Lab at The Johns Hopkins School of Medicine in Baltimore.

RICHARD HUGANIR, PhD—is Professor and Director of the Solomon H. Snyder Department of Neuroscience and Director of the Kavli Neuroscience Discovery Institute at The Johns Hopkins School of Medicine in Baltimore.

KEN PALLER, PhD—is a professor of psychology and Director of the Cognitive Neuroscience Program at Northwestern University in Evanston, Illinois, who studies the relationship between sleep and memory in humans.

The following is an edited transcript of their roundtable discussion. The participants have been provided the opportunity to amend or edit their remarks.

THE KAVLI FOUNDATION: Dr. Cirelli, to begin, tell us about your most recent paper exploring sleep and memory.

Chiara Cirelli studies one of the ultimate biological mysteries: why we sleep. She proposed the idea that the function of sleep is to reset the strength of synapses, the junctions between neurons, in the brain.

CHIARA CIRELLI: With my colleague Giulio Tononi, we published a paper on our latest attempt to test whether sleep is the time when neural connections—or synapses—are reset after a day’s worth of learning. We think this reset process helps to make synapses more efficient and restores balance to the system. Using a powerful microscope, we measured the size of about 7000 synapses in images we’d taken of mouse brains, after the animals had slept or had been awake for several hours.

TKF: And what did you find?

CIRELLI: We found evidence that sleep does streamline these neural connections. The size of synapses gives us an idea of how much information is flowing between brain cells. We found that relative to mice that had been awake and learning, mice that had had a chance to sleep after learning showed an 18 percent decrease in synapse size.

TKF: This is an idea you proposed about 15 years ago. What prompted it?

CIRELLI: Our rationale has always been that whatever sleep does, it must be something very important and difficult, if not impossible, to perform during waking. Otherwise, why does the brain disconnect from the environment for long periods of time every day? And why has it been maintained across evolution even though it is a very dangerous state for an animal? Ultimately, what’s the purpose of sleep?

The idea that we have been testing, called the "synaptic homeostasis hypothesis" of sleep, is that when we’re awake and confronting the environment around us, we are always learning something. This learning brings about changes in the structure and function of the brain: the connections between neurons get stronger. But this plasticity comes with a very high price, and that price is energy. A lot of the brain’s energy budget is used by synapses. Also, synaptic strength can’t increase indefinitely. Eventually, synapses become saturated and we therefore lose the ability to learn anything new. This is a well-recognized problem and one that many researchers think the brain is designed to take care of. However, most scientists think that the problem can’t be solved “online”: every time some synapses get strengthened, others get weakened, so that the total amount of synaptic strength remains balanced. We, instead, think that across a 24-hour cycle, is a perfect time to learn and for synaptic strength to go up overall, during waking, and a perfect time for it to go down overall, during sleep. That’s why we think sleep is so important.

"Our rationale has always been that whatever sleep does, it must be something very important and difficult, if not impossible, to perform during waking. Otherwise, why does the brain disconnect from the environment for long periods of time every day?"—Chiara Cirelli

TKF: Why has this idea been so hard to test?

CIRELLI: There is no single, “perfect” way to measure synaptic strength; [instead], there are several complementary methods, some more direct than others, and it is necessary to use many of them to obtain a reliable assessment. One approach is to measure the proteins that are expressed in synapses and are crucial for their functioning, as we did, and as was done by Drs Huganir and Diering did. Another is to measure the size of synapses, because stronger synapses are also bigger.

TKF: Dr. Huganir and Dr. Diering, you set out to test Dr. Cirelli’s idea that neurons have a way to balance synaptic strength. What have you recently discovered?

Richard Huganir's research focuses on the mechanisms of synaptic plasticity, the constant change in the strength of the connections between brain cells that underlies learning and memory.

RICK HUGANIR: Our results were very similar to Chiara's. We found that synapses, which are made of proteins and other molecules, sort of disassemble during sleep and then reassemble during wakeful periods. They do this in a proportional manner that retains a lot of the information learned during the day, but also resets the synapses enough that the brain is ready to learn the next day.

My lab has been studying synaptic plasticity—the various ways the connections between neurons change as we learn—for more than 20 years. In our recent study, we were particularly interested in a specific form of plasticity, called homeostatic plasticity, which is the way the brain maintains its energy balance so that it operates efficiently. Most of our studies have been done in tissue culture, where we grow neurons in a dish and study the various molecules and proteins involved in these synaptic changes. We were looking for a way to test whether homeostatic plasticity really occurs in live animals, and Graham came up with the idea that a great place to look for it would be during sleep.

GRAHAM DIERING: I was very much inspired by Chiara and Giulio’s hypothesis. That’s what kicked off this work. I was looking for molecular changes in the brain during sleep that mirrored the observations we had made for many years in the cultured neurons.

TKF: Dr. Diering, you’ve compared the brain to an Etch-A-Sketch pad. What do you mean by that?

Colorized 3D reconstruction of dendrites, the tree-like branches of neurons. By studying thousands of images like this one, Chiara Cirelli and her team showed that, in the mouse brain, synapses shrink during sleep and grow again during wakeful periods. (Credit: Wisconsin Center for Sleep and Consciousness).

DIERING: If you think about it, over a lifetime, the storage capacity of a human brain is vast. But on any given day, the amount of information that can be stored is limited. So you really have to have a regular rejuvenation process. An Etch-A-Sketch comes to mind because once you’ve filled it with doodles, there is a nice little mechanism—a quick shake—to clean it off so you can start drawing anew. The brain does the same thing, but in a more sophisticated way. The brain eliminates some of the little doodles we make in the day, such as what we have for breakfast, but protects and stores the most important ones for later. Our research suggests that that rejuvenation takes place while we sleep.

TKF: Do we need a whole night’s sleep to reset the brain or is a 20-minute nap enough?

CIRELLI: I suspect that a nap, especially one that that reaches the deepest stages of sleep that we think are most restorative, is going to make a difference, but we haven’t done the experiments.

More and more, we realize that the quality not just the quantity of sleep is important. Many labs are trying to enhance or disrupt specific brainwaves that occur during different stages of sleep to manipulate sleep quality. Those experiments might give us answers to how much sleep and what kind of sleep is needed to maximize our ability to learn and remember.

HUGANIR: We’d like to do that experiment. We’ve developed a new technique that allows us to image synapses in the brains of live animals, so we can watch synapses in the same animal day after day after day and study how they change. It is a very powerful tool that will help us a look at what’s happening during different periods of the sleep-wake cycle, including the different stages of sleep.

"If you think about it, over a lifetime, the storage capacity of a human brain is vast. But on any given day, the amount of information that can be stored is limited. So you really have to have a regular rejuvenation process.... Our research suggests that that rejuvenation takes place while we sleep."—Graham Diering

TKF: Dr. Paller, you’ve studied the relationship between sleep and memory in people. Do the results of these experiments fit what you’ve learned about the benefits of sleep?

KEN PALLER: Certainly. It’s been great to see these advances in understanding the molecular mechanisms involved in brain plasticity and their connection to sleep. Chiara also brought up the need to understand sleep physiology—what neural mechanisms are engaged during different sleep stages, and what roles those mechanisms play in memory processing. I agree with her that that’s exactly how we might build from the work we’re discussing.

TKF: Dr. Diering, let’s go back to one of your experiments—the one where you blocked the brain’s ability to reset during sleep. What were the consequences for the mice?

Graham Diering led a study suggesting that a lack of sleep inhibits the brain's abiity to form new memories. He is a post-doctoral fellow in the lab of Richard Huganir at the John Hopkins School of Medicine.

DIERING: The mice were confused. They couldn’t distinguish between different environments—specifically, a place where they had received a foot shock and should be fearful of, and another place where they had had not received a foot shock. In both places, they froze in their tracks, which is an instinctive behavior in rodents when they are afraid. We think this means that the downscaling of synapses that we and Chiara’s team saw helps to clarify memories and add specificity to them. That’s part of the memory-consolidation process, in which newly acquired memories are turned into long-term memories.

TKF: Does this mean our own memories get muddled when we don’t get enough sleep?

CIRELLI: The sleep field has convincingly shown that sleep helps us remember some things and forget other things that aren’t so important. But how this happens at the synaptic level in people is still very difficult to figure out. We’ve done computer simulations that demonstrate streamlining neural connections during sleep leads to all kinds of advantages, such as making some information more salient and removing some of the noise—the unimportant information we take in—to increase the potential for new learning.

PALLER: Another angle to this is how sleep changes as we age and how that influences memory. As we grow older, sleep quality tends to decline. So it could be that age-related memory decline arises partly because memory consolidation during sleep isn’t working quite as well as it used to in young adulthood. That possibility has steadily appeared more and more likely.

The evidence available so far suggests that sleep is going to be part of the story of aging and memory decline. In one of our studies, for example, we examined memory and sleep in patients in the very early stages of Alzheimer’s disease. We saw a connection between how well they could remember verbal details from the previous day with how well they had slept during the intervening night. So nighttime consolidation of memories apparently contributed to memory problems they experienced the next day.

"[W]e need new approaches to help people sleep better, and to treat sleep disorders. And it might not be in the form of new sleep drugs. Rather, we need basic research to help us understand how memories are consolidated during sleep."—Ken Paller

TKF: Dr. Paller, is it true that we’re actually organizing and selecting memories for long-term storage while we’re asleep?

Ken Paller's research suggests that memories can be reactivated and strengthened during sleep. He is part of a team, funded by the BRAIN Initiative, that is studying how sleep determines the fate of individual memories.

PALLER: Yes, we think that memory retrieval is key to making memories endure, and that it happens not just when we are awake—perhaps intentionally remembering a person’s name or how to navigate to some location—but also when we are asleep. So that complements the story of forgetting. As we’re forgetting some information, we’re also preferentially reactivating some information. This intervening retrieval may be a fundamental part of why we remember some things while forgetting many others. The reactivation process may also help certain memories to become richer and stronger, as they become integrated together with other previously stored knowledge.

TKF: So sleep acts as a kind of filter, selecting some memories to retain while discarding others?

PALLER: That’s right. And the door is open for research to determine whether memory reactivation during sleep is one of the key steps that differentiates what we retain and what we forget.

In my lab, we’ve taken on this challenge by running experiments provoking reactivation during sleep by reminding people of things they recently learned. Essentially, we use sensory cues—smells or sounds connected with prior learning—in a way that doesn’t arouse people from their sleep. They don’t wake up but their brains are working, memories are reactivated, and that reactivation changes memory storage. That’s a way for us to try to understand the mechanisms that are involved in memory consolidation during sleep.

HUGANIR: In rodents, there is a replay phenomenon—a kind of dreaming that recreates the day’s events. By recording from a brain region called the hippocampus, it is possible to watch a rat or mouse “thinking” about, or replaying, the events of the day. That phenomenon is consistent with what Dr. Paller is saying about memory reactivation in humans.

The question of how these two systems interact—the scaling back of synapses, but also this replay that occurs in selective networks to consolidate certain memories—during sleep is really fascinating. We’re scaling down a lot of synapses and forgetting some things, while strengthening other connections. That could be an area of future research for us.

CIRELLI: Another task for the future is to bridge the gap between animal studies, in which we look at memory over very short time scales, perhaps 24 hours, and human studies. Our memories are extremely long-lasting, so we need to figure out how to test the role of sleep in memory over longer periods of time.

"It’s amazing that our synapses are dissembling and reassembling every day during sleep. It’s a remarkable biological process."—Richard Huganir

TKF: How do you plan to build on these findings?

As an animal learns, the junctions between brain cells, or synapses (in green), grow stronger. Richard Huganir and his team have developed a way of watching synapses form in the mouse brain in real time. (Credit: Huganir Lab/Hopkins Medicine)

CIRELLI: Well, I don’t know of a brain region that is not plastic, so I would like to test whether this reset process also happens in regions other than the ones most commonly associated with memory. I would also like to study the role of sleep in the developing brain. Young animals, including infants, spend most of their time asleep. Is sleep doing something different in the developing brain, while is still growing and forming synapses? That’s a completely open question.

HUGANIR: We’re very interested in the interactions between different forms of plasticity. We want to study how chemicals released by brain cells called neuromodulators selectively influence one form of plasticity or another. Many of these chemicals are also involved in sleep.

We will also continue using our new imaging technique to study synapses in various areas of the brain during sleep and different forms of plasticity.

DIERING: The question that really has my attention right now is: what’s the role of sleep as the brain is developing? And, if we have a condition that prevents us from sleeping properly, how is that going to affect the development of the brain and our behavior?

I think the health implications of this research are really exciting. The kind of research we’ve been discussing today could lead to new treatments for sleep disorders. If we can understand what’s happening in the brain during sleep, we might be able to develop medicines that will help us sleep better. The sleep drugs available today help us fall asleep, but they don’t enhance sleep quality. They weren’t designed with a real understanding of what’s happening in the brain during sleep. I think there’s a lot room for therapies to help us benefit the most from sleep, especially in disease conditions.

HUGANIR: The current treatments actually disrupt homeostatic plasticity. Sleep drugs are usually benzodiazepines, and they wreak havoc on synaptic scaling, at least in the tissue culture models that we’ve looked at.

CIRELLI: Which is not surprising given that sleep is a very complicated process. None of our current medications mimic real sleep.

PALLER: I agree with Graham that we need new approaches to help people sleep better, and to treat sleep disorders. And it might not be in the form of new sleep drugs. Rather, we need basic research to help us understand how memories are consolidated during sleep. Investigations of the physiology of sleep, which we can monitor by measuring various brain oscillations, is giving us clues about how memories are replayed and integrated in the human brain. The physiology is intricate and elegant, so high-precision manipulations are required. These investigations are thus leading to new ideas about how to make the relevant sleep physiology run more efficiently. Using electrical and acoustic stimulation, for example, my colleagues and I have been working to non-invasively enhance these oscillations and memory consolidation.

TKF: Given your research, can I assume that you all get at least 8 hours of shut-eye every night?

CIRELLI: I’ve been a true believer in sleep from the very beginning. Everybody knows that I love to have people over for dinner, but by about 9:30 pm I’m gone! So, nothing has changed for me except that I keep getting confirmation. These latest studies show that within a few hours the structure of your brain is literally changing during sleep. But frankly I didn’t need this new evidence to think that sleep is very important.

HUGANIR: As a scientist, I think it’s an occupational hazard to be sleep-deprived. But I must say, it’s amazing that our synapses are dissembling and reassembling every day during sleep. It’s a remarkable biological process.